Selective Inhibitors of GSK3-beta

Case ID: 01100

Case ID:

01100

Web Published:

1/31/2017

Description

Technology

Glycogen synthase kinase 3 (GSK3) is a ubiquitously expressed serine/threonine kinase that is being investigated clinically for a variety of therapeutic applications including CNS disorders, metabolic disorders and in dental health.

Centrally, GSK3 is primarily responsible for aberrant phosphorylation of tau leading to pathological tau and dementias such as Alzheimer’s disease (AD), frontotemporal dementia, progressive supranuclear palsy, and CTE. It is also being studied as a therapeutic for the treatment of bipolar disorders and autism.

As part of the insulin pathways GSK inhibition downregulates glycogen synthase, which converts glucose to glycogen for storage.

Collagen sponges infused with GSK3 inhibitors have been shown to promote the formation of dentine, leading to a complete repair of dental caries.1 Such regenerative endodontics may be the shortest path to market for GSK3 inhibitors.

GSK3-beta is a high potential target for the treatment of neurodegenerative diseases such as AD and CTE, as well as for type II diabetes, some types of cancer, and for regenerative endodontics.

Inventors identified a natural product inhibitor of GSK3-beta via functional screening (IC50 = 185 micromolar) and improved potency and ADMET properties by preparing a small set of semi-synthetic analogs using structure-guided design. These inhibitors are not competitive with ATP and bind in the substrate binding cavity similar to tideglusib which is in multiple clinical trials. Potency is similar to tideglusib with IC50 about 600 nM. The optimized lead shows good microsomal stability, cell permeability and ADMET properties.

Proposal

The University of Hawai‘i seeks a cooperative research agreement to further optimize this lead series or seeks to out-license this technology.